1. Field of the Invention
With the increased level of understanding concerning the immune response process in mammals, there is a growing awareness that certain molecules play a significant role in immune modulation. Unfortunately, these molecules are generally nonspecific as to their effects on single cell types in a mixture of cells. A critical need exists for agonists that are effect or cell specific.
Histamine is a small molecule that has been shown to have a significant role in the immune response process in mammals. However, its ubiquitous effects on many cells that have receptors for histamine limits its possible immunotherapeutic use. Histamine derivatives that are tissue directed or effect specific would significantly aid in determining the role of histamine in immune modulation and produce valuable immunotherapeutics.
Histamine can substantially modulate models of immune responses in mammals, particularly models of delayed hypersensitivity and T and B cell functions. Histamine is synthesized during different phases of response to antigen and is able directly or indirectly to effect further responses to antigen. It is possible that the concentration of histamine in tissue during inflammation and immune response can modify the function of a number of lymphoid cells. Although these effects may be substantial, the direct effects on single cell types in a mixture of cells cannot be determined unless the agonists are effect or cell specific. Ubiquitous effects of agonists on all cells that have receptors for histamine would limit any immunotherapeutic use of histamine. See Khan, et al., Clin.Immunol. Rev. (1985) 4:1 Melmon, et al., Am. J. Med. (1981) 71:100: and Rocklin et al., Cell Immunol. (1978) 37:162.
Histamine is an autacoid as are catecholamines, prostaglandins and some peptides, e.g., bradykinin and probably lymphokines. Autacoids differ from hormones in that they are made at their local sites of action and they can be made in a variety of tissues. Autacoids play an important role in mediating inflammation. During inflammation, certain events may occur which include: protein denaturation, lowering of local pH, release of "new peptides" and lysosomal enzymes, and the like. Such events create a setting in which the immune system should not overreact to the new products. Yet, despite the ability of inflammation to generate likely immunogens, the inflammatory process usually is not accompanied or followed by grossly abnormal immune responses. Autacoids appear to somehow modulate this response.
Autacoids affect natural suppressor cells, T cell subsets, and B cells during various stages of immunity. Receptors for autacoids are non-randomly distributed (in number and affinity for agonist) on cells that carry out immune functions. Precursor B cells do not appear to have histamine and catecholamine receptors, while B cells committed to produce antibodies do. T suppressor (T.sub.s cells modulate the CAMP responses of T helper (T.sub.h) and T cytolytic (T.sub.c) cells to histamine. Mitogens alter responsiveness of these cells to histamine. Some lymphocytes that respond to histamine have both H.sub.1 and H.sub.2 receptors on them while others only have H.sub.2 receptors. In some lymphocytes the H.sub.2 receptors seem to modify the responses to H.sub.1 agonism: in others there is no such interplay. In some cells biologic response is inhibitory (e.g., reduced release of antibody from B cells: inhibition of lymphokine release or lysis of target cells by T effector cells and inhibition of release of histamine from mast cells): in others the response enhances immune function (e.g., enhanced suppression by natural suppressor and T.sub.s cells or T.sub.h cell proliferation). The autacoids seem to be enhancing selected early events in immune response (e.g., enhanced suppressor function) while inhibiting later phases of phenotypic manifestations (e.g., release of lymphokines or antibodies) of immunity.
The appearance of naturally occurring suppressor cells in the spleens of neonatal or irradiated mice may have a key role in induction of immune tolerance. See, Strober et al., Ann. Rev. Immunol. (1984) 2:219: Hertel-Wulff et al., J. Immunol. (1984) 133:2791: Okada et al., J. Expt. Med. (1982) 156:522: and Okada et al., J. Immunol. (1982) 129:1892. These cells are related to NK cells in terms of their surface phenotype but differ in function. The natural suppressor cells appear briefly during the early maturation of lymphoid tissue but can be induced in adults by total lymphoid irradiation. The cells have the unique feature of inhibiting the antigen-specific cytolytic arm of alloreactive immune response but leave the antigen-specific suppressive arm intact. In this way, alloreactions in the regulatory milieu of natural suppressor (NS) cells generate large numbers of antigen-specific suppressor cells that in turn maintain tolerance in vivo. Thus, the natural suppressor cells may play an important role in preventing the development of host versus graft and graft versus host diseases in allogeneic bone marrow chimeras, and in immune tolerances in the neonatal and total lymphoid irradiated (TLI) mice.
Histamine activates human T.sub.s cells and enhances the suppressive ability of murine NS cells in vitro. See, Khan et al., J. Immunol. (1985) 134:4100 and Sansoni et al., J. Clin. Invest. (1985) 75:650. After pretreatment of human T.sub.s cells (Leu-2., 9.3 ) with histamine, both phytohemagglutinin-induced T.sub.h cell proliferation and pokeweed mitogen-induced B cell differentiation were inhibited. The effects were mediated via H.sub.2 receptors. The enhancement of natural suppressor function is via H.sub.1 receptors. Natural suppressor cells can be propagated and cloned in long-term tissue culture and cause nonspecific suppression in both in vitro and in vivo models of mixed leukocyte reactions. Therefore, it is important to develop histamine derivatives which can affect the ability of NS cells to modulate graft versus host reaction in vivo.
2. Brief Description of the Relevant Art
Strategies have been developed for derivatizing catecholamines that are relevant to the subject invention, the relevant parts of which are herein incorporated by reference. See, Rosenkranz et al., Mol. Pharmacol. (1983) 24:429: Jacobson et al., Intl. J. Pept. Protein Res. (1983) 22:284: Verlander et al., Biopolymers (1983) 22:531: Rosenkranz et al., J. Pharmacol. Exp. Ther. (1983) 227:267: Jacobson et al., J. Med. Chem. ( 983) 26:492: and U.S. Pat. No. 4,337,207.